VRML Models for Analysing Chemical Structure-Activity Relationships.

Christopher Leach and Henry S. Rzepa

Department of Chemistry, Imperial College, London, SW7 2AY.

One novel application of VRML models is in revealing in a simple visual manner complex structure-activity relationships. Take for example the structures and conformations of a simple molecule such as 1, which can depend greatly on the relative energies of intramolecular hydrogen bonding between the substituents and the overall stabilisation of the molecule by solvation.1 These factors in turn depend on geometrical features such as the axial/equatorial conformation of the molecule, the relative orientation of the hydroxyl groups to eachother and to the substituent, and bulk factors such as the polarity of the solvent. All these effects can be modelled nowadays using quantitative methods based on quantum mechanic treatment of the molecule, but such modelling produces a lot of data that has to be interpreted in terms of simple effects.

To reduce the complexity and enhance any small features from all this data, we proceeded as follows. Firstly, the energies were calculated as the difference between heats of formation obtained for a model with a solvent permittivity (dielectric) e=1 (gas phase) and one with e=80 (water).2 In such a model, we expect an essentially constant solvation energy will be obtained for molecules where intra-molecular hydrogen bonding does not alter as a function of geometry, but a variable solvation energy if intra-molecular hydrogen bonding did vary according to the conformation of the substituents.

To enable the computed energy differences to be easily interpreted and associated with individual molecular geometries, the were presented as VRML models showing a 3D contour map. The dihedral angles of the two hydroxyl groups were plotted as the X and Y axes and the computed solvation energy was on the Z axis. The results (PM3 method) for R = 4-methoxyphenyl in the triaxial conformation rapidly revealed to us that prominent intra-molecular p-facial hydrogen bonding occurred at geometries associated with two peaks in the potential surface coded as purple, along with two less prominent peaks associated with O-H...O interactions. The various regions of the potential surfaces can have hyperlinks to 3D coordinates, allowing the reader to explore the geometric features of interest to them simply by clicking with their mouse button at the feature of interest. The VRML model also superimposes the tri-equatorial surface (green-yellow regions), where the lack of any intramolecular hydrogen bonding renders the surface almost entirely flat. A surface intersection can be seen, corresponding to a region where the axial and equatorial isomers are of equal energy.

Substituent effects can be enhanced by subtracting one potential surface from another (e.g. 1, R=H vs R=4-methoxyphenyl). Here, the prominent purple ridges now correspond to geometries where hydrogen bonding from the hydroxyl groups to the p face of the aromatic ring occurs (right).
Other unexpected effects can also be discovered using this technique. For example, altering the the electron demand of the aryl p face from a donor to an acceptor (R = 4-nitrophenyl) results in significant stabilisation by oxygen lone pair donation from the hydroxyl oxygen atoms to the face of the aryl group (left), identified by the different position of the purple ridge.
The advantage of using a VRML model to express the energetics and geometrical features of such systems is that this allows the reader to explore the features of interest to them, and not necessarily those noted and analysed by the original authors.

  1. R. J. Abraham, E. J. Chambers and W. A. Thomas, J. Chem. Soc, Perkin Trans. 2, 1993, 1061.
  2. H. S. Rzepa, C. Leach and O. Casher, Proc. 1st Electronic Comp. Chem. Conference (ECCC-1), CD ROM Version, ARInternet Corp., Landover, Md., 1995.